Project Summary Esophageal squamous cell carcinoma (ESCC) is the second leading cause of cancer-related death among males in East Africa. In southwestern Uganda, the prevalence of ESCC is increasing while the mean age of diagnosis is decreasing. In addition, ESCC continues to be complicated by late presentation and poor survival rates despite therapy. These changing prevalence and age of onset cannot be explained by known ESCC risk factors including human papillomavirus, alcohol and tobacco use as the prevalence of these risk factors remains low and unchanged. Additional, potentially modifiable risk factors that are contributing to the increase in ESCC have yet to be elucidated. Polycyclic aromatic hydrocarbons exposures in biomass fuel and/or dietary sources are potential explanations of the heightened risk of ESCC in sub-Saharan Africa. The current K43 application seeks to build on previous cross-sectional work that demonstrates male sex, smoking and alcohol as risk factors for ESCC. First, the award will provide the opportunity to strengthen my understanding of measurement and analysis of nutritional data, cancer and genetic epidemiology, and to complete successful apprenticeships with leading experts in cancer genomics, gastroenterology, and nutrition. The proposed training will include brief courses offered through Harvard University and Mbarara University of Science and Technology. Second, my cohort of ESCC patients will enable prospective examination of relationships of polycyclic aromatic hydrocarbon exposures with ESCC. I will also explore genetic and molecular signatures of ESCC in this population. The proposed career development activities and series of studies will deepen our understanding of the biological mechanisms through which biomass fuel and diet affects ESCC risk, with a primary focus on DNA methylation as a mediator. These findings can provide new understanding of pathways to ESCC that may lead to innovative ways to encourage multifactorial risk factor modification in individuals living in ESCC high burden areas in sub-Saharan Africa, a public health goal that has been difficult to attain.